Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia

Abstract Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in...

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Autores principales: Sebastian Friedrich, Hannah Müller, Caroline Riesterer, Hannah Schüller, Katja Friedrich, Carlotta Leonie Wörner, Tilman Busch, Amandine Viau, E. Wolfgang Kuehn, Michael Köttgen, Alexis Hofherr
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/26259eef2f0a4eac970d8c986bd2bb91
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spelling oai:doaj.org-article:26259eef2f0a4eac970d8c986bd2bb912021-12-02T16:50:24ZIdentification of pathological transcription in autosomal dominant polycystic kidney disease epithelia10.1038/s41598-021-94442-82045-2322https://doaj.org/article/26259eef2f0a4eac970d8c986bd2bb912021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94442-8https://doaj.org/toc/2045-2322Abstract Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Here we performed transcriptomic analyses of Pkd1- and Pkd2-deficient mIMCD3 kidney epithelial cells followed by a meta-analysis to integrate all published ADPKD transcriptomic data sets. Based on the hypothesis that Pkd1 and Pkd2 operate in a common pathway, we first determined transcripts that are differentially regulated by both genes. RNA sequencing of genome-edited ADPKD kidney epithelial cells identified 178 genes that are concordantly regulated by Pkd1 and Pkd2. Subsequent integration of existing transcriptomic studies confirmed 31 previously described genes and identified 61 novel genes regulated by Pkd1 and Pkd2. Cluster analyses then linked Pkd1 and Pkd2 to mRNA splicing, specific factors of epithelial mesenchymal transition, post-translational protein modification and epithelial cell differentiation, including CD34, CDH2, CSF2RA, DLX5, HOXC9, PIK3R1, PLCB1 and TLR6. Taken together, this model-based integrative analysis of transcriptomic alterations in ADPKD annotated a conserved core transcriptomic profile and identified novel candidate genes for further experimental studies.Sebastian FriedrichHannah MüllerCaroline RiestererHannah SchüllerKatja FriedrichCarlotta Leonie WörnerTilman BuschAmandine ViauE. Wolfgang KuehnMichael KöttgenAlexis HofherrNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Sebastian Friedrich
Hannah Müller
Caroline Riesterer
Hannah Schüller
Katja Friedrich
Carlotta Leonie Wörner
Tilman Busch
Amandine Viau
E. Wolfgang Kuehn
Michael Köttgen
Alexis Hofherr
Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
description Abstract Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Here we performed transcriptomic analyses of Pkd1- and Pkd2-deficient mIMCD3 kidney epithelial cells followed by a meta-analysis to integrate all published ADPKD transcriptomic data sets. Based on the hypothesis that Pkd1 and Pkd2 operate in a common pathway, we first determined transcripts that are differentially regulated by both genes. RNA sequencing of genome-edited ADPKD kidney epithelial cells identified 178 genes that are concordantly regulated by Pkd1 and Pkd2. Subsequent integration of existing transcriptomic studies confirmed 31 previously described genes and identified 61 novel genes regulated by Pkd1 and Pkd2. Cluster analyses then linked Pkd1 and Pkd2 to mRNA splicing, specific factors of epithelial mesenchymal transition, post-translational protein modification and epithelial cell differentiation, including CD34, CDH2, CSF2RA, DLX5, HOXC9, PIK3R1, PLCB1 and TLR6. Taken together, this model-based integrative analysis of transcriptomic alterations in ADPKD annotated a conserved core transcriptomic profile and identified novel candidate genes for further experimental studies.
format article
author Sebastian Friedrich
Hannah Müller
Caroline Riesterer
Hannah Schüller
Katja Friedrich
Carlotta Leonie Wörner
Tilman Busch
Amandine Viau
E. Wolfgang Kuehn
Michael Köttgen
Alexis Hofherr
author_facet Sebastian Friedrich
Hannah Müller
Caroline Riesterer
Hannah Schüller
Katja Friedrich
Carlotta Leonie Wörner
Tilman Busch
Amandine Viau
E. Wolfgang Kuehn
Michael Köttgen
Alexis Hofherr
author_sort Sebastian Friedrich
title Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
title_short Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
title_full Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
title_fullStr Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
title_full_unstemmed Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
title_sort identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/26259eef2f0a4eac970d8c986bd2bb91
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